Aminoindane derivatives as serotonin and norepinephrine uptake inhibitors

ABSTRACT

The present invention relates to aminoindane derivatives having the formula I wherein X, Y, U, R 1-2 , R 13-16  and R are as defined in the claims, or an acid addition salt thereof. The compounds of the invention posses the combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition.

The invention provides novel aminoindane derivatives which are useful inthe treatment of affective disorders, such as depression and anxietydisorders.

BACKGROUND OF THE INVENTION

The combined effect of serotonin reuptake inhibition and norepinephrineuptake inhibition on depression is explored in clinical studies ofcompounds such as Duloxetine (Wong DT: Duloxetine (LY-248686): aninhibitor of serotonin and noradrenaline uptake and an antidepressantdrug candidate Expert Opinion on Investigational Drugs (1998) 7 101691-1699) and Venlafaxine (Khan-A; Fabre-LF; Rudolph-R: Venlafaxine indepressed outpatients Psychopharmacology Bulletin (1991) 27, 141-144).

The present invention provides novel compounds which posses the combinedeffect of serotonin reuptake inhibition and norepinephrine uptakeinhibition for the treatment of affective disorders, such as depression,anxiety disorders including general anxiety disorder, social anxietydisorder, post traumatic stress disorder, obsessive compulsive disorder,panic disorder, panic attacks, specific phobias, social phobia andangoraphobia.

SUMMARY OF THE INVENTION

The present invention relates to compounds having the formula I

wherein

-   X is —O—, —S— or —CR⁴R⁵—;-   Y is —CR⁶R⁷—, —CR⁶R⁷—CR⁸R⁹—or —CR⁶═CR⁷—; or X and Y together form a    group—-   CR⁴═CR⁵—, or —CR⁴═CR⁵—CR⁶R⁷—; and-   U is —O—, —S— or CR¹⁰R¹¹; or-   X is —O—, —S— or —CR⁴R⁵—; and-   Y and U together form a group CR⁶═CR⁷—, —CR⁶═CR⁷—CR¹⁰R¹¹—,-   or —CR⁶R⁷—CR¹⁰═CR¹¹—;-   or X and Y and U together form —CR⁴═CR⁵—CR⁶═CR⁷—;

R¹ and R² are independently selected from hydrogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, or R¹ and R² together withthe nitrogen, to which they are attached, form a 3-7-membered saturatedring optionally containing one further heteroatom;

-   R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen,    halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, and    C₃₋₈-cycloalkyl;-   R is hydrogen, halogen, C₁₋₆-alkyl or cyano;-   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected    from hydrogen and C₁₋₄-alkyl;-   or an acid addition salt thereof;

The invention also provides a pharmaceutical composition comprising acompound of formula I or a pharmaceutically acceptable acid additionsalt thereof and at least one pharmaceutically acceptable carrier ordiluent.

The invention further provides the use of a compound of formula I or apharmaceutically acceptable acid addition salt thereof for thepreparation of a medicament for the treatment of affective disorders,such as depression and anxiety disorders including general anxietydisorder, social anxiety disorder, post traumatic stress disorder,obsessive compulsive disorder, panic disorder, panic attacks, specificphobias, social phobia and angoraphobia.

The invention also provides a method for the treatment of an affectivedisorder as mentioned above in a living animal body, including a human,comprising administering a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable acid additionsalt thereof.

DETAILED DESCRIPTION OF THE INVENTION

According to one specific embodiment of the invention, X and U isselected from —O— and —S— and Y is —CR⁶R⁷—or —CR⁶R⁷—CR⁸R⁹—.

According to another specific embodiment of the invention, X and Y and Utogether form —CR⁴═CR⁵—CR⁶═CR⁷—.

Preferred compounds according to the invention are:

-   Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine,-   Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine,-   Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)diethylamine,-   Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)diethylamine,-   Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)ethylamine,-   Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)ethylamine,-   Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)methylamine,-   Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)methylamine,-   (+)-trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine,-   (−)-trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine,-   (+)-cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine,-   (−)-cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine,-   Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-methyl-amine,-   Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-methyl-amine,-   Cis-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-indan-1-yl]-dimethyl-amine,-   Trans-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-indan-1-yl]-dimethyl-amine,-   Cis-Dimethyl-(3-naphthalen-2-yl-indan-1-yl)-amine,-   Trans-Dimethyl-(3-naphthalen-2-yl-indan-1-yl)-amine,-   Cis-[3-(6-Chloro-benzo[1,3]dioxol-5-yl)-indan-1-yl]-dimethyl-amine,-   Trans-[3-(6-Chloro-benzo[1,3]dioxol-5-yl)-indan-1-yl]-dimethyl-amine,-   Cis-[3-(6-Chloro-benzo[1,3]dioxol-5-yl)-indan-1-yl]-methyl-amine,-   Trans-[3-(6-Chloro-benzo[1,3]dioxol-5-yl)-indan-1-yl]-methyl-amine,-   Cis-Enantiomer-1-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-methyl-amine    and-   Cis-Enantiomer-2-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-methyl-amine    or acid addition salts thereof.

As used herein halogen means fluoro, chloro, bromo or iodo.

The term C₁₋₆ alkyl refers to a branched or unbranched alkyl grouphaving from one to six carbon atoms inclusive, such as methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and2-methyl-1-propyl.

Similarly, C₂₋₆ alkenyl and C₂₋₆ alkynyl, respectively, designate suchgroups having from two to six carbon atoms including one double bond andtriple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl,propynyl, and butynyl.

The term C₃₋₈ cycloalkyl designates a monocyclic or bicyclic carbocyclehaving three to eight C-atoms, such as cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

R¹ and R² may together with the nitrogen atom to which they are attachedform a 3-7 membered ring optionally containing one further heteroatom,such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl and piperazinyl.

Exemplary of organic acid addition salts according to the invention arethose formed with maleic, fumaric, benzoic, ascorbic, succinic, oxalic,bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,propionic, tartaric, salicylic, citric, gluconic, lactic, malic,mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic,glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophyllineacetic acids, as well as the 8-halotheophyllines, for example8-bromotheophylline. Exemplary of inorganic acid addition saltsaccording to the invention are those formed with hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The acidaddition salts of the invention are preferably pharmaceuticallyacceptable salts formed with non-toxic acids.

The compounds of this invention may exist in unsolvated as well as insolvated forms with pharmaceutically acceptable solvents such as water,ethanol and the like. The solvated forms are considered equivalent tothe unsolvated forms for the purposes of this invention.

Some of the compounds of the present invention contain chiral centresand such compounds exist in the form of isomers (e.g. enantiomers ordiastereomers). The invention includes all such isomers and any mixturesthereof including racemic mixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods, for example, by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Racemic compounds of the presentinvention can thus be resolved into their optical antipodes, e.g., byfractional crystallisation of d- or 1-(tartrates, mandelates orcamphorsulphonate) salts for example. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix.

The compounds of the present invention may also be resolved by theformation of diastereomeric derivatives or by enzymatic resolvation.

Additional methods for the resolution of optical isomers, known to thoseskilled in the art, may be used. Such methods include those discussed byJ. Jaques, A. Collet and S. Wilen in “Enantiomers, Racemates, andResolutions”, John Wiley and Sons, New York (1981).

Optically active compounds can also be prepared from optically activestarting materials.

The compounds of the invention may be prepared by:1) Alkylating an Amine of Formula III with an Alkylating Reagent ofFormula II:

wherein R, R¹-R², R¹³⁻¹⁶, X, Y and U are as previously defined, and L isa leaving group such as halogen, mesylate or tosylate;2) Reductive Alkylation of an Indane Ketone of Formula IV with an Amineof Formula III:

wherein R, R¹-R², R¹³⁻¹⁶, X, Y and U are as previously defined;3) Opening an Epoxide of Formula V with an Amine of Formula III:

wherein R, R¹-R², R¹³⁻¹⁶, X, Y and U are as previously defined.

The alkylation according to method 1) is conveniently performed in anorganic solvent such as an alcohol or ketone with a suitable boilingpoint, preferably in the presence of an organic or inorganic base(potassium carbonate, diisopropylethylamine or triethylamine) at refluxtemperature. Alternatively, the alkylation can be performed at a fixedtemperature, which is different from the boiling point, in one of theabove-k mentioned solvents or in dimethyl formamide (DMF),dimethylsulfoxide (DMSO) or N-methylpyrrolidin-2-one (NM), preferably inthe presence of a base such as those mentioned above. The alkylatingderivatives of formula II have been described in the literature (e.g.Bøgesø, K. P. J. Med. Chem. 26, 1983, 935-947; Bøgesø, K. P. et al. J.Med. Chem. 28, 1985, 1817-1828: Sommer, M. B. et al. J. Org. Chem. 55,1990, 4822-4827 and references cited therein) and the amines of formulam are commercially available.

The reductive alkylation according to method 2) is performed by standardliterature methods. The reaction can be performed in one step understandard reductive amination conditions using e.g. sodiumcyanoborohydride or in two steps, e.g. by condensation of amines offormula m with a reagent of formula IV followed by reduction of theresulting imine with sodium cyanoborohydride or sodium borohydride. Theketones of formula IV can be prepared as described in the literature(e.g. BΠgesΠ, K. P. J. Med. Chem. 26, 1983, 935-947; BΠgesΠ, K. P. etal. J. Med. Chem. 28, 1985, 1817-1828; Sommer, M. B. et al. J. Org.Chem. 55, 1990, 4822-4827 and references cited therein).

The epoxide opening according to method 3) is conveniently performed inan organic solvent such as a suitably boiling alcohol or ketone using anexcess of an amine of formula III at reflux temperature.

Epoxides of formula IV can be prepared by methods described in theliterature (e.g. Ghosh, A. K. et al. Synthesis 5; 1997; 541-544; Palmer,M. J. et al.; J. Chem. Soc. Perkin Trans. 1, 2002, 416-427).

The pharmaceutical formulations of the invention may be prepared byconventional methods in the art. For example: Tablets may be prepared bymixing the active ingredient with ordinary adjuvants and/or diluents andsubsequently compressing the mixture in a conventional tablettingmachine. Examples of adjuvants or diluents comprise: corn starch, potatostarch, talcum, magnesium stearate, gelatine, lactose, gums, and thelike. Any other adjuvants or additives usually used for such purposessuch as colourings, flavourings, preservatives etc. may be used providedthat they are compatible with the active ingredients.

Solutions for injections may be prepared by dissolving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to desiredvolume, sterilising the solution and filling it in suitable ampules orvials. Any suitable additive conventionally used in the art may beadded, such as tonicity agents, preservatives, antioxidants, etc.

The pharmaceutical compositions of this invention or those which aremanufactured in accordance with this invention may be administered byany suitable route, for example orally in the form of tablets, capsules,powders, syrups, etc., or parenterally in the form of solutions forinjection. For preparing such compositions, methods well known in theart may be used, and any pharmaceutically acceptable carriers, diluents,excipients or other additives normally used in the art may be used.

Conveniently, the compounds of the invention are administered in unitdosage form containing said compounds in an amount of about 0.01 to 100mg. The total daily dose is usually in the range of about 0.05-500 mg,and most preferably about 0.1 to 50 mg of the active compound of theinvention.

Experimental

The compounds of the invention exemplified in the following have beencharacterized using the following methods:

Melting points were determined on a Büchi B-540 apparatus and areuncorrected. Mass spectra were obtained on a Quattro MS-MS system fromVG Biotech, Fisons Instruments. Analytical LC-MS data were obtained on aPE Sciex API 150EX instrument equipped with IonSpray source andShiinadzu LC-8A/SLC-10A LC system. The LC conditions (50×4.6 mm YMCODS-A with 5 μm particle size) were linear gradient elution withwater/acetonitrile/trifluoroacetic acid (90:10:0.05) towater/acetonitrile/trifluoroacetic acid (10:90:0.03) in 7 min at 2mL/min. Purity was determined by integration of the UV trace (254 nm).The retention times R_(t) are expressed in minutes. PreparativeLC-MS-separation was performed on the same instrument. The LC conditions(50×20 mm YMC ODS-A with 5 μm particle size) were linear gradientelution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) towater/acetonitrile/trifluoroacetic acid (5:95:0.03) in 7 min at 22.7mL/min. Fraction collection was performed by split-flow MS detection.

¹H NMR spectra were recorded at 250.13 MHz on a Bruker AC 250 or at500.13 MHz on a Bruker DRX 500. Deuterated chloroform (99.8% D) ordimethylsulfoxide (99.9% D) were used as solvents. TMS was used asinternal reference standard. Chemical shifts are expressed as ppmvalues. The following abbreviations are used for multiplicity of NMRsignals: s=singlet, d=doublet, 1-triplet, q=quartet, qv=quintet,h=heptet, dd=double doublet, dt-double triplet, dq=double quartet,t-triplet of triplets, m=multiplet, b=broad. NMR signals correspondingto acidic protons are to some extent omitted. Content of water incrystalline compounds was determined by Karl Fischer titration. Forcolumn chromatography, silica gel of type Kieselgel 60, 40-60 mesh ASTMwas used. For ion-exchange chromatography, the following material wasused: SCX-columns (1 g) from Varian Mega Bond Elut®, Chrompack cat. No.220776. Prior to use, the SCX-columns were pre-conditioned with 10%solution of acetic acid in methanol (3 mL).

EXAMPLES

Preparation of Intermediates

A. Alkylating Reagents

3-Amino-1-(benzo[1,3]dioxol-5-yl)-1-cyano-1H-indene-2-carboxylic AcidMethyl Ester

A mixture of 2-chlorobenzonitrile (12.3 g) andbenzo[1,3]dioxol-5-yl-acetonitrile (10 g) in dimethylformamide (25 mL)was added with stirring and cooling in an ice bath to potassiumtert-butoxide (20.1 g) dissolved in dimethylformamide (50 mL) at such arate that the temperature did not exceed 25° C. After stirring for 0.5h, methyl chloroacetate (11.1 g) was added in 10 min. After beingstirred for 24 h at rt, the mixture was poured into a mixture of 0.1 MHCl (200 mL), heptane (30 mL) and toluene (15 mL). Stirring for 1 h,filtration and washing with water (2×50 mL), toluene (2×10 mL) andheptane (2×25 mL) afforded 79% of3-Amino-1-benzo[1,3]dioxol-5-yl-1-cyano-1H-indene-2-carboxylic acidmethyl ester.

3-(Benzo[1,3]dioxol-5-yl)-indan-1-one

A mixture of3-amino-1-benzo[1,3]dioxol-5-yl-1-cyano-1H-indene-2-carboxylic acidmethyl ester (10 g) and acetic acid, (30 mL) were heated to 100° C.; 60%aqueous sulfuric acid (20 mL) was added with stirring during 30 min. Themixture was heated to 110° C. for 6 h, cooled to rt, extracted withtoluene (50+10 mL), washed with water (3×100 mL), extracted with 0.1 Maqueous sodium hydroxide (100+20 mL), acidified with concentratedhydrochloric acid, extracted with toluene (25+10 mL), and filtratedthrough activated carbon. Removal of the toluene gave 80% of1-(benzo[1,3]dioxol-5-yl)-3-oxo-indan-1-carboxylic acid. The acid wassubsequently decarboxylated by heating to 100° C. in N-methylpyrrolidone(15 mL) for 1 h. After cooling, the solution was poured into water (40mL) with efficient stirring. Filtration, washing with water (5×20 mL),dissolution in ethyl acetate (40 mL), filtration through activatedcarbon and removal of the ethyl acetate gave 80% of3-(benzo[1,3]dioxol-5-yl)-indan-1-one.

Cis-3-(benzo[1,3]dioxol-5-yl)-indan-1-ol

Sodium borohydride (1.5 g) was added in portions with stirring at 10-15°C. to a solution of 3-(benzo[1,3]dioxol-5-yl)-indan-1-one (10 g) in amixture of ethanol (75 mL) and dimethoxyethane (75 mL). The mixture wasstirred at rt for 1 h and then evaporated in vacuo. The resulting oilwas treated with water and diethyl ether, and the organic phase wasseparated and washed with water and 0.1 N HCl, dried (MgSO4) andevaporated in vacuo to give cis-3-(benzo[1,3]dioxol-5-yl)-indan-1-ol asa brown oil (10 g).

5-(3-Chloro-indan-1-yl)-benzo[1,3]dioxole

Thionyl chloride (7 mL) was added with stirring and cooling at 15° C. toa solution of cis-3-(benzo[1,3]dioxol-5-yl)-indan-1-ol (10 g) indichloromethane (300 mL). The mixture was stirred at rt for 40 min. Themixture was washed twice with water, dried (MgSO4) and evaporated invacuo to give a quantitative yield of5-(3-chloroindan-1-yl)benzo[1,3]dioxole as an oil, which was used in thenext step without further purification.

Preparation of the Compounds of the Invention

Example 1 trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine(1) andcis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine (2)

A mixture of 5-(3-chloroindan-1-yl)-benzo[1,3]dioxole (11 g) and 70 mLof 33% dimethylamine in ethanol was kept at 100° C. in a steel autoclavefor 16 h. The mixture was cooled and evaporated in vacuo. The residuewas dissolved in diethylether and washed with water and 2 N NaOH. Theorganic phase was dried (magnesium sulphate) evaporated in vacuo and theresidue was purified by flash chromatography on silicagel using agradient-eluent: 1) ethyl acetate/heptane (80:20) and 2) ethylacetate/ethanol/triethylamine (90:10:4) to give the crude products asclear oils.

Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine(1)

The slow-eluting compound is the trans isomer (3 g).

¹H NMR (CDCl₃): 1.95-2.05 (m, 1H); 2.30 (s, 6H); 2.60-2.70 (m, 1H); 4.40(m, 2H); 5.90 (s, 2H); 6.55 (m, 1H); 6.65 (m, 1H), 6.70 (m, 1H), 6.95(m, 1H), 7.25 (m, 1H), 7.45 (m, 1H). The compound could be converted tothe fumarate salt from ethyl acetate/ethanol as a white crystallinecompound.

Cis-(3-Benzo[1.3]dioxol-5-yl-indan-1-yl)dimethylamine(2)

The fast-eluting compound is the cis isomer (1 g).

¹H NMR (CDCl₃): 1.95-2.05 (m, 1H); 2.30 (s, 6H); 2.60-2.70 (m, 1H); 4.10(m, 1H); 4.45 (m, 1H), 5.90 (s, 2H); 6.55 (m, 1H); 6.65 (m, 1H), 6.70(m, 1H), 6.95 (m, 1H), 7.25 (m, 1H), 7.45 (m, 1H). The compound could beconverted to the fumarate salt from ethyl acetate/ethanol as a whitecrystalline compound.

The following compounds 3-14 were prepared analogously, HPLC-retentiontime and purity are described in table 1.:

-   Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)diethylamine(3)-   Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)diethylamine(4)-   Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)ethylamine(5)-   Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)ethylamine(6)-   Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)methylamine(7)-   Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)methylamine(8)-   Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-methyl-amime (13)-   Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-methyl-amine(14)-   Cis-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-indan-1-yl]-dimethyl-amine    (15)-   Trans-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-indan-1-yl]-dimethyl-amine(16)-   Cis-Dimethyl-(3-naphthalen-2-yl-indan-1-yl)-amine(17)-   Trans-Dimethyl-(3-naphthalen-2-yl-indan-1-yl)-amine(18)-   Cis-[3-(6-Chloro-benzo[1,3]dioxol-5-yl)-indan-1-yl]-dimethyl-amine(19)-   Trans-[3-(6-Chloro-benzo[1,3]dioxol-S-yl)-indan-1-yl]-dimethyl-amine(20)-   Cis-[3-(6-Chloro-benzo[1,3]dioxol-5-yl)-indan-1-yl]-methyl-amine(21)

Trans-[3-(6-Chloro-benzo[1,3]dioxol-5-yl)-indan-1-yl]-methyl-amine(22)TABLE 1 Retention time Purity % Compound (min) Purity % (UV) (ELSD) 11.88 85.18 99.12 2 1.9 93.92 99.26 3 1.83 99.25 99.72 4 1.87 95.85 99.695 1.58 100 95.80 6 1.73 86.91 99.74 7 1.79 94.36 99.59 8 1.86 95.3499.70 13 1.83 78.3 98.1 14 1.89 81.8 93.3 15 1.73 78.1 99.8 16 1.68 84.792.7 17 2.10 92.5 99.8 18 2.10 92.8 99.9 19 2.08 75.1 97.7 20 1.89 96.499.7 21 2.08 81.8 96.3 22 2.00 86.8 97.1 23 1.83 82.4 99.1 24 1.87 77.398.5

Example 2 (+)-trans-(3-Benzo[1.3]dioxol-5-yl-indan-1-yl)dimethylamine(9)and (−)-trans-(3-Benzo[1.3]dioxol-5-yl-indan-1-yl)dimethylamine(10)

Compound 1, trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine, wassubjected to resolution by chiral HPLC using a Gilson SF3 supercriticalfluid chromatography system equipped with chiralcelOD columns (4.6 mm×25cm for analytical and 10 mm×25 cm for preparative runs). The particlesize in the columns was 10 μm. A solution of compound 1,trans-(3-benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine, (1 g) inmethanol (1 nmL1) was injected in 40 μL portions on a preparativecolumn. The column was eluted with carbondioxide—modifier (75:25). Themodifier was 2-propanol with diethylamine(0.5%) and trifluoracetic acid(0.5%). The flow was 18.9 mL/min at 20 Mpa. Fraction collection wastriggered by UV-detection (210 nM). The fractions containing theseparate products were pooled and evaporated in vacuo which gave theenantiomers 9 and 10.

-   (+)-trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine(9):    a=+14.0 (conc.=1% in Methanol)-   (−)-trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine(10):    a=−14.7 (conc.=1% in Methanol).

Example 3 (+)-cis-(3-Benzo[1.3]dioxol-5-yl-indan-1-yl)dimethylamine(11)and (−)-cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine(12)

Compound 2, cis-(3-benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine, wassubjected to resolution by chiral HPLC using a Gilson SF3 supercriticalfluid chromatography system equipped with chiralcelOD columns (4.6 mm×25cm for analytical and 10 mm×25 cm for preparative runs). The particlesize in the columns was 10 μM. A solution of compound 2,cis-(3-benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine, (1 g) in methanol(1 mL) was injected in 40 μL portions on a preparative column. Thecolumn was eluted with carbondioxide—modifier (75:25). The modifier was2-propanol with diethylamine (0.5%) and trifluoracetic acid (0.5%). Theflow was 18.9 mL/min at 20 Mpa. Fraction collection was triggered byUV-detection (210 nM). The fractions containing the separate productswere pooled and evaporated in vacuo which gave the enantiomers 11 and12.

-   (+)-cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine(11): at    =+3.3 (conc.=1% in Methanol)-   12. (−)-cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine(12):    a=−4.4 (conc.=1% in Methanol).    The following Compounds were Prepared Analogously:-   (+)—Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-methyl-amine(23)-   (−)—Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-methyl-amine(24).    Pharmacological Testing

The compounds of the invention were tested in well-recognised andreliable tests. The tests were as follows:

Measurements of [³H]noradrenaline Uptake into Rat Cortical Synaptosomes.

Fresh cortex from male Wistar rats (125-225 g) are homogenized in 0.32 Msucrose supplemented with 1 mM nialamid with a glass/teflon homogenizer.The homogenate is centrifuged at 600×g for 10 min at 4° C. The pellet isdiscarded and the supernatant is centrifuged at 20.000×g for 55 min. Thefinal pellet is homogenized (20 sec) in this assay buffer (6 mg originaltissue/mL=4 mg/well). Test compounds (or buffer) and 10 nM[³H]-noradrenaline are added to deep 96 well plates and shaken briefly.Composition of assay buffer: 123 mM NaCl, 4.82 mM KCl, 0.973 mM CaCl₂,1.12 mM MgSO₄, 12.66 mM Na₂BPO₄, 2.97 mM NaH₂PO₄, 0.162 mM EDTA, 10 mMglucose and 1 mM ascorbic acid. Buffer is oxygenated with 95% O₂/5% CO₂for 10 min at 37° C. and pH is adjusted 7.4. The incubation is startedby adding tissue to a final assay volume of 1 ml. After 15 minincubation with radioligand at 37° C., samples are filtered directly onUnifilter GF/C glass fiber filters (soaked for 1 hour in 0.1%polyethylenimine) under vacuum and immediately washed with 3×1 mL assaybuffer. Non-specific uptake is determined using talsupram (10 μM finalconcentration). Duloxetine is included as reference in all experimentsas dose-response curve.

Measurements of [³H]-5-HT Uptake into Rat Cortical Synaptosomes.

Whole brains from male Wistar rats (125-225 g), excluding cerebellum,are homogenized in 0.32 M sucrose supplemented with 1 mM nialamid with aglass/teflon homogenizer. The homogenate is centrifuged at 600×g for 10min at 4° C. The pellet is discarded and the supernatant is centrifugedat 20.000×g for 55 min. The final pellet is homogenized (20 sec) in thisassay buffer (0.5 mg original tissue/well). Test compounds (or buffer)and 10 nM [³H]-5-HT are added to 96 well plates and shaken briefly.Composition of assay buffer: 123 mM NaCl, 4.82 mM KCl, 0.973 mM CaCl₂,1.12 mM MgSO₄, 12.66 mM Na₂BPO₄, 2.97 mM NaH₂PO₄, 0.162 mM EDTA, 10 mMglucose and 1 mM ascorbic acid. Buffer is oxygenated with 95% O₂/5% CO₂for 10 min at 37° C. and pH is adjusted 7.4. The incubation is startedby adding tissue to a final assay volume of 0.2 mL. After 15 minincubation with radioligand at 37° C., samples are filtered directly onUnifilter GF/C glass fiber filters (soaked for 1 hour in 0.1%polyethylenimine) under vacuum and immediately washed with 3×0.2 mlassay buffer. Non-specific uptake is determined using citalopram (10 μMfinal concentration). Citalopram is included as reference in allexperiments as dose-response curve.

Results of the experiments shoved that the compounds of the inventionshowed that the compounds all inhibit the norepinephrine and serotonineuptake with IC₅₀ below 200 nM.

1. An aminoindane compound having the formula I

wherein X is —O—, —S— or —CR⁴R⁵—; Y is —CR⁶R⁷—, —CR⁶R⁷—CR⁸R⁹— or—CR⁶═CR⁷—; or X and Y together form a group — CR⁴═CR⁵—, or—CR⁴═CR⁵—CR⁶R⁷—, and U is —O—, —S— or CR¹⁰R¹¹; or X is —O—, —S— or—CR⁴R⁵—; and Y and U together form a group CR⁶═CR⁷—, —CR⁶═CR⁷—CR¹⁰R¹¹—,or —CR⁶R⁷—CR¹⁰═CR¹¹—; or X and Y and U together form —CR⁴═CR⁵—CR⁶═CR⁷—;R¹ and R² are independently selected from hydrogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, or R¹ and R² together withthe nitrogen, to which they are attached, form a 3-7 membered ringoptionally containing one further heteroatom; R¹³, R¹⁴, R¹⁵ and R¹⁶ areeach independently selected from hydrogen, halogen, cyano, nitro,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, and C₃₋₈-cycloalkyl; R ishydrogen, C₁₋₆-alkyl or cyano; R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ areeach independently selected form hydrogen and C₁₋₄-alkyl; or an acidaddition salt thereof.
 2. A compound according to claim 1 wherein X andU is selected from —O— and —S— and Y is —CR⁶R⁷⁻ or —CR⁶R⁷-CR⁸R⁹—.
 3. Acompound according to claim 1 wherein X and Y and U together form—CR⁴═CR⁵—CR⁶═CR⁷—.
 4. A compound according to claim 1 which isTrans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-dimethyl-amine,Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-dimethyl-amine,Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-diethyl-amine,Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-diethyl-amine,Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-amine,Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-amine,Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-methyl-amine,Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-methyl-amine,(+)-trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-dimethyl-amine,(−)-trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-dimethyl-amine,(+)-cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-dimethyl-amine,(−)-cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-dimethyl-amine,Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-methyl-amine,Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-methyl-amine,Cis-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-indan-1-yl]-dimethyl-amine,Trans-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-indan-1-yl]-dimethyl-amine,Cis-Dimethyl-(3-naphthalen-2-yl-indan-1-yl)-amine,Trans-Dimethyl-(3-naphthalen-2-yl-indan-1-yl)-amine,Cis-[3-(6-Chloro-benzo[1,3]dioxol-5-yl)-indan-1-yl]-dimethyl-amine,Trans-[3-(6-Chloro-benzo[1,3]dioxol-5-yl)-indan-1-yl]-dimethyl-amine,Cis-[3-(6-Chloro-benzo[1,3]dioxol-5-yl)-indan-1-yl]-methyl-amine,Trans-[3-(6-Chloro-benzo[1,3]dioxol-5-yl)-indan-1-yl]-methyl-amine,Cis-Enantiomer-1-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-methyl-amine ndCis-Enantiomer-2-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-methyl-amine or anacid addition salt thereof.
 5. A pharmaceutical composition comprising acompound according to claims 1 to 4 or a pharmaceutically acceptableacid addition salt thereof and at least one pharmaceutically acceptablecarrier or diluent.
 6. The use of a compound according to claims 1 to 4or a pharmaceutically acceptable acid addition salt thereof for thepreparation of a medicament for the treatment of affective disorders,such as depression and anxiety disorders including general anxietydisorder, social anxiety disorder, post traumatic stress disorder,obsessive compulsive disorder, panic disorder, panic attacks, specificphobias, social phobia and angoraphobia.
 7. A method for the treatmentof an affective disorder, including depression and anxiety disordersincluding general anxiety disorder, social anxiety disorder, posttraumatic stress disorder, obsessive compulsive disorder, panicdisorder, panic attacks, specific phobias, social phobia andangoraphobia in a living animal body, including a human, comprisingadministering a therapeutically effective amount of a compound accordingto claims 1 to 4 or a pharmaceutically acceptable acid addition saltthereof.